Ketoacidosis is a frequent complication of insulin dependent (i.e. juvenile onset) diabetes and has been associated with depressed glucose and increased ketone body utilization in the brain and in some cases a decreased CMRO2. However, attempts to correlate the metabolic depression with increased cerebral ketone body metabolism have not produced a clear relationship. Thus, other factors may be involved. Up to now most studies have been conducted in animals during acute (less than 1 week) diabetic ketoacidosis. However, interpretations from these studies have been complicated by use of anesthetics (in some cases) and varying tissue sampling procedures. In addition, these studies have provided little (or no) information on changes in cerebral lipid and protein metabolism, enzyme activities, or mitochondrial function. There is abundant evidence that significant impairment of these is present in other body tissues. Furthermore, the role of insulin in affecting cerebral metabolism is far from being resolved. This includes conditions where plasma insulin is either increased (systemic administration) or decreased (poorly controlled diabetes). The proposed research will be directed toward evaluating, in the awake goat, cerebral glucose (i.e. glycolytic, glycogen, pentose phosphate, TCA cycle) and oxidative (primarily mitochondrial) metabolism, activities of key enzymes, and, to a limited degree, lipid and protein metabolism during poorly controlled diabetes. The principal aims will be to study: 1) the degree of metabolic impairment as a function of severity of ketoacidosis, number of ketoacidotic episodes, levels of insulin in brain tissue and ECF, and age of onset; 2) what metabolic pathways are being affected (and specific sites); and 3) the efficacy of insulin treatment. Studies here will be made regarding specific effects of insulin on cerebral metabolism in normal and diabetic goats, using both intracerebral and systemic administration and the degree of metabolic recovery following insulin (i.e. are some changes irreversible?). The sampling of tissue in awake goats will involve the use of a chronically implanted cranial window. For almost all analyses, samples will be removed frozen (-40 - -90 C freon cooled probe). Results from the proposed experiments should provide new insights into the pathogenesis of diabetes in the brain.